Bisphosphonates (BP) are a class of anti-resorptive drugs that target metabolic bone diseases characterized by accelerated states of skeletal turnover, such as post-menopausal osteoporosis. BPs have a high affinity for hydroxyapatite in bone matrix where it is released and incorporated by the osteoclast during bone resorption. Once intracellular, the BP disrupts osteoclast function. To generate a BP with optimal activity and potency, numerous BPs have been developed by chemically modifying side chains. Alternatively, we hypothesize that conjugation of BP to Vitamin B6 will improve the BP incorporation by osteoclasts. Vitamin B6 is a known facilitator of prodrug transport into cells and itsnatural metabolic pathway may enhance the intracellular release of BPs. We propose to test, in an ovariectomized rat model for post-menopausal osteoporosis, whether our proposed conjugation of a BP increases its potency. Specific Aims are 1) to synthesize MBC-4, a conjugate of Vitamin B6 and pamidronate, for animal experimentation, 2) to characterize the skeletal response to MBC-4 with a) bone histomorphometry and b) biomechanical testing and 3) to compare the lowest effective doses of MBC-4 to prevent bone loss and the reduction of mechanical properties to an optimal dose of non-conjugated pamidronate as a proof-of-principle. [unreadable] [unreadable] [unreadable]